Trial Comparing Infliximab and Infliximab and Azathioprine in the Treatment of Patients With Crohn's Disease na�ve to Both Immunomodulators and Biologic Therapy (Study of Biologic and Immunomodulator Naive Patients in Chrohn's Disease: SONIC

• ClinicalTrials.gov Identifier: NCT00094458
• Recruitment Status: Completed
• First Posted: October 20, 2004
• Results First Posted: June 23, 2009
• Last Update Posted: February 9, 2017
• Sponsor: Centocor Ortho Biotech Services, L.L.C.
• Collaborator: Schering-Plough
• Information provided by (Responsible Party): Centocor Ortho Biotech Services, L.L.C.

Tracking Information

• First Submitted Date: October 19, 2004
• First Posted Date: October 20, 2004
• Results First Submitted Date: April 30, 2009
• Results First Posted Date: June 23, 2009
• Last Update Posted Date: February 9, 2017
• Study Start Date: March 2005
• Actual Primary Completion Date: April 2008 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 15, 2016)

Percentage of Participants With Corticosteriod-free Clinical Remission [ Time Frame: Week 26 ]

Corticosteroid-free clinical remission is defined as a Crohn's Disease Activity Index (CDAI) less than (<) 150 in participants who have not received any dose of systemic corticosteroids (prednisone or equivalent) for greater than or equal to (>=) 3 weeks and have not received budesonide at a dose > 6 milligram per day (mg/day) for >= 3 weeks. The total CDAI score ranges from 0 - 600. The lower the CDAI score, the better (i.e., 0 is better and 600 is worse).

• Original Primary Outcome Measures (submitted: June 23, 2005): Steroid-free remission

Current Secondary Outcome Measures (submitted: December 15, 2016)

• Percentage of Participants With Mucosal Healing [ Time Frame: Week 26 ]
  Complete absence of mucosal ulcerations in the colon and terminal ileum as assessed by video endoscopy.
• Percentage of Participants With Corticosteroid-free Clinical Remission (Study Extension) [ Time Frame: Week 50 ]
  Corticosteroid-free clinical remission is defined as a Crohn's Disease Activity Index (CDAI) < 150 who have not received any dose of systemic corticosteroids (prednisone or equivalent) for >= 3 weeks and have not received budesonide at a dose > 6 milligram per day (mg/day) for >= 3 weeks. The total CDAI score ranges from 0 - 600. The lower the CDAI score, the better (i.e., 0 is better and 600 is worse).
• Percentage of Participants With Clinical Remission (Main Study) [ Time Frame: Weeks 2, 6, 10, 18 and 26 ]
  Clinical remission is defined as a CDAI < 150, compared to baseline (Week 0)
• Percentage of Participants With Clinical Remission (Study Extension) [ Time Frame: Weeks 34, 42 and 50 ]
  Clinical remission is defined as a CDAI < 150, compared to baseline (Week 0)
• Percentage of Participants With Clinical Response Over Time (Main Study) [ Time Frame: Weeks 2, 6, 10, 18, 26 ]
  Clinical response, defined as a >=100-point decrease in CDAI from Baseline.
• Percentage of Participants With Clinical Response Over Time (Study Extension) [ Time Frame: Weeks 34, 42, 50 ]
  Clinical response, defined as a >=100-point decrease in CDAI from Baseline.
• Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Weeks 2, 6, 10, 18 and 26 (Main Study) [ Time Frame: Baseline and Weeks 2, 6, 10, 18, 26 ]
  Quality of life as measured by the Inflammatory Bowel Disease Questionnaire (IBDQ). The IBDQ is a 32- item questionnaire and the total IBDQ score can range from 32 (very poor) to 224 (perfect).
• Average Corticosteroid Use [ Time Frame: Weeks 2, 6, 10, 18 and 26 ]
  Average daily dose of systemic corticosteroid concomitant medications(prednisone or equivalent)

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Trial Comparing Infliximab and Infliximab and Azathioprine in the Treatment of Patients With Crohn's Disease na�ve to Both Immunomodulators and Biologic Therapy (Study of Biologic and Immunomodulator Naive Patients in Chrohn's Disease: SONIC
• Official Title: Multicenter, Randomized, Double-Blind, Active Controlled Trial Comparing REMICADE� (Infliximab) and REMICADE Plus Azathioprine to Azathioprine in the Treatment of Patients With Crohn's Disease Naive to Both Immunomodulators and Biologic Therapy
• Brief Summary: The purpose of this study is to assess the safety and effectiveness of three different treatments for patients with Crohns disease who have not responded to previous treatment with a group of drugs commonly used to treat Crohn's Disease (5-ASA) and corticosteroids. Patients will receive either infliximab (a drug used to treat autoimmune diseases) or azathioprine (an immunosuppressant or drug used to suppress the immune system) or a combination of both for up to 34 weeks. This research study will involve approximately 500 patients. The main study involves up to 34 weeks (approximately 8 months). A study extension of an additional 20 weeks (approximately 5 months) is optional for patients who successfully complete the main study. A country-specific study extension of open label infliximab treatment for an additional 1 year is optional for patients who successfully complete the main study extension.
• Detailed Description: Crohns disease is characterized by inflammation (the changes that happen when tissues in the body are injured) and ulceration (open sores) of the intestines. Crohns disease is treated with medications that decrease inflammation, and reduce diarrhea, abdominal pain and other symptoms of Crohns disease. In addition, Crohns disease can be treated with medications that suppress the immune system (the body system involved in inflammation and infections) or with surgery. This study will investigate the effectiveness of infliximab and azathioprine in the treatment of patients with moderate-to-severe Crohns disease. Infliximab is currently approved by the FDA for the treatment of both Crohns disease and rheumatoid arthritis. Azathioprine, which is an investigational drug, has not been approved by the FDA for the treatment of Crohns disease, but it is a well-established therapy that has been used for many years to treat Crohns disease. This study seeks to determine whether infliximab, azathioprine, or the combination of both drugs would be the most appropriate treatment for Crohns disease patients who have not responded well to certain drugs called 5-ASA drugs (e.g. Asacol, Pentasa, sulfasalazine) and/or require frequent treatment with corticosteroids. This research study will involve approximately 500 patients. Patients may participate in the main study for up to 34 weeks (approximately 8 months). During the main study, patients will be asked to visit the study center for 10 visits. If patients enroll into the extension of the study, the total time for participation may be up to 54 weeks (approximately 13 months). Patients enrolled in the Study Extension will be asked to visit the study center for an additional 5 visits. A country-specific (EU and Israel only), prospective, multi-center, open-label extension of the study will further evaluate the long-term safety and efficacy of scheduled maintenance therapy with infliximab in patients with Crohns Disease. Patients who have completed treatment through Week 50 in the SONIC main study and who, in the opinion of the investigator, would benefit from infliximab treatment may enter the open-label extension. Patients will be randomly assigned to one of three treatment groups (either infliximab plus placebo capsules, infliximab plus azathioprine, or azathioprine plus placebo infusions - there is no possibility of being assigned to placebo only in this trial - patients will receive one or both of these medications) at the beginning of the study. Oral medication will be taken daily. There are 5 infusion (which will be either infliximab or placebo) visits during the main study.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Crohn Disease

Intervention

• Biological: infliximab infusion; AZA placebo caps
  Infliximab 5 mg/kg at weeks 0, 2, 6, 14, and 22 and placebo AZA capsules
• Other: infliximab (IFX) infusion; azathioprine (AZA) caps
  AZA daily 2.5 mg/kg/day and IFX infusions 5 mg/kg at weeks 0, 2, 6, 14, and 22
• Drug: infliximab (IFX) placebo infusion; azathioprine (AZA) caps
  AZA daily 2.5 mg/kg/day and placebo IFX infusions at weeks 0, 2, 6, 14, and 22

Study Arms

• Experimental: 003
  infliximab (IFX) infusion; azathioprine (AZA) caps AZA daily 2.5 mg/kg/day and IFX infusions 5 mg/kg at weeks 0, 2, 6, 14, and 22
  Intervention: Other: infliximab (IFX) infusion; azathioprine (AZA) caps
• Experimental: 001
  infliximab (IFX) placebo infusion; azathioprine (AZA) caps AZA daily 2.5 mg/kg/day and placebo IFX infusions at weeks 0, 2, 6, 14, and 22
  Intervention: Drug: infliximab (IFX) placebo infusion; azathioprine (AZA) caps
• Experimental: 002
  infliximab infusion; AZA placebo caps Infliximab 5 mg/kg at weeks 0, 2, 6, 14, and 22 and placebo AZA capsules
  Intervention: Biological: infliximab infusion; AZA placebo caps

Publications *

• Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D, Lichtiger S, D'Haens G, Diamond RH, Broussard DL, Tang KL, van der Woude CJ, Rutgeerts P; SONIC Study Group. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med. 2010 Apr 15;362(15):1383-95. doi: 10.1056/NEJMoa0904492.
• Colombel JF, Adedokun OJ, Gasink C, Gao LL, Cornillie FJ, D'Haens GR, Rutgeerts PJ, Reinisch W, Sandborn WJ, Hanauer SB. Combination Therapy With Infliximab and Azathioprine Improves Infliximab Pharmacokinetic Features and Efficacy: A Post Hoc Analysis. Clin Gastroenterol Hepatol. 2019 Jul;17(8):1525-1532.e1. doi: 10.1016/j.cgh.2018.09.033. Epub 2018 Sep 26.
• Colombel JF, Reinisch W, Mantzaris GJ, Kornbluth A, Rutgeerts P, Tang KL, Oortwijn A, Bevelander GS, Cornillie FJ, Sandborn WJ. Randomised clinical trial: deep remission in biologic and immunomodulator naïve patients with Crohn's disease - a SONIC post hoc analysis. Aliment Pharmacol Ther. 2015 Apr;41(8):734-46. doi: 10.1111/apt.13139. Epub 2015 Mar 1.
• Reinisch W, Colombel JF, Sandborn WJ, Mantzaris GJ, Kornbluth A, Adedokun OJ, Miller M, Tang KL, Rutgeerts P, Cornillie F. Factors associated with short- and long-term outcomes of therapy for Crohn's disease. Clin Gastroenterol Hepatol. 2015 Mar;13(3):539-547.e2. doi: 10.1016/j.cgh.2014.09.031. Epub 2014 Sep 19.
• Peyrin-Biroulet L, Reinisch W, Colombel JF, Mantzaris GJ, Kornbluth A, Diamond R, Rutgeerts P, Tang LK, Cornillie FJ, Sandborn WJ. Clinical disease activity, C-reactive protein normalisation and mucosal healing in Crohn's disease in the SONIC trial. Gut. 2014 Jan;63(1):88-95. doi: 10.1136/gutjnl-2013-304984. Epub 2013 Aug 23.
• Ferrante M, Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D, Lichtiger S, D'Haens GR, van der Woude CJ, Danese S, Diamond RH, Oortwijn AF, Tang KL, Miller M, Cornillie F, Rutgeerts PJ; International Organization for the Study of Inflammatory Bowel Diseases. Validation of endoscopic activity scores in patients with Crohn's disease based on a post hoc analysis of data from SONIC. Gastroenterology. 2013 Nov;145(5):978-986.e5. doi: 10.1053/j.gastro.2013.08.010. Epub 2013 Aug 14.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 4, 2009): 508
• Original Enrollment (submitted: June 23, 2005): 500
• Actual Study Completion Date: December 2009
• Actual Primary Completion Date: April 2008 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Diagnosis of Crohns Disease for at least 6 weeks
• Moderate to severe disease activity (CDAI >= 220 and <=450)
• No history of azathioprine, 6-MP (6 Mercaptopurine), or biologic treatments
• Are either: Corticosteriod-dependent, OR considered for a 2nd (or greater) course of corticosteriod, OR 5-ASA failures, Or Budesonide failures

Exclusion Criteria:

• History of abdominal surgery within the last 6 months
• Have an ostomy or stoma [An operation to create an opening from an area inside the body to the outside]
• Are pregnant, nursing, or planning pregnancy (both men and women)
• Serious simultaneous illness that could interfere with study participation
• Use of any investigational drug within 30 days
• Have a concomitant diagnosis or any history of congestive heart failure
• Weigh more than 140 kilograms (or 310 pounds)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 21 Years to 99 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Austria, Belgium, Canada, Denmark, France, Germany, Greece, Israel, Netherlands, Norway, Portugal, Spain, Sweden, United Kingdom, United States

Administrative Information

• NCT Number: NCT00094458
• Other Study ID Numbers: CR004804; C0168T67
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Centocor Ortho Biotech Services, L.L.C.
• Study Sponsor: Centocor Ortho Biotech Services, L.L.C.
• Collaborators: Schering-Plough

Investigators

• Study Director: Centocor Ortho Biotech Services, L.L.C. Clinical Trial; Centocor Ortho Biotech Services, L.L.C.

• PRS Account: Centocor Ortho Biotech Services, L.L.C.
• Verification Date: December 2016